myotonic dystrophy - IDMC.org

Abstract No : 26
ORAL PRESENTATIONS
TRANSCRIPTIONAL PROFILE OF TRANSGENIC MICE EXPRESSING
AN EXPANDED CUG REPEAT
Osborne R.J., Welle S. and Thornton C.A.
University of Rochester, Department of Neurology, Rochester (NY), USA, 16642
HSALR transgenic mice expressing CUG expansion RNA in skeletal muscle have a DM-like
phenotype. For several genes these mice replicate the abnormal regulation of alternative
splicing seen in DM. In an attempt to identify additional pathways affected by
repeat expansion RNA, we used expression microarrays to compare skeletal muscle in
two independent founder lines of HSALR mice (lines 20b and 41) and in wild-type (WT)
mice of the same genetic background (n=6 per group, no sample pooling). To obtain
comprehensive coverage of the mouse transcriptome we used Affymetrix 430A and B
chips (45,000 probe sets). These analyses identified 45 probe sets that were differentially
expressed in both HSALR20b and HSALR41 versus WT comparisons (P≤0.01, foldchange
≥2). We postulated that some of these changes resulted from responses to
myotonic discharges or nonspecific muscle injury. To eliminate these genes from consideration,
we also studied adr (ClC-1 null) mice and their WT controls (n=3 per group, no
sample pooling). We chose adr mice because they have severe myotonia and modest upregulation
of regeneration dependent genes. After filtering out probe sets showing similar
changes in adr and HSALR mice, we were left with 24 genes that were up-regulated
and 4 genes that were down-regulated in both HSALR founder lines. Of note, none of
these genes have been previously implicated in DM pathogenesis. We conclude that the
influence of poly(CUG) accumulation on gene expression is surprisingly restricted, even
in myonuclei that have a heavy burden of repeat expansion RNA. The function of these
genes suggests signaling pathways that might be involved in the DM disease process.
QUEBEC 2005 47